P540: PEVONEDISTAT, AZACITIDINE AND VENETOCLAX FOR PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA– A PHASE I STUDY
Authors: G. S. Guru Murthy, S. Kaufmann, A. Saliba, A. Szabo, L. Michaelis, S. Abedin, L. Runaas, K. Carlson, S. Maldonado-Schmidt, A. Hinman, A. Thomas, A. Baim, M. Litzow, E. Atallah
Journal: HemaSphere (2022)

Background: Outcomes of patients with relapsed/refractory acute myeloid leukemia (RR-AML) have remained poor. Venetoclax therapy in RR-AML is associated with lower complete remission (CR) as compared to newly diagnosed AML. Preclinical studies suggest overexpression of anti-apoptotic MCL-1 as a mechanism of BCL-2 inhibitor resistance (Konopleva et al. Cancer Cell 2006). Pevonedistat is a first in class inhibitor of Nedd8 activating enzyme that induces pro-apoptotic NOXA leading to neutralization of MCL-1 and apoptosis. In preclinical AML models, combination of pevonedistat and venetoclax showed synergistic effect (Knorr KL et al. Cell Death Differ. 2015). Aims: To assess the safety and outcomes of adding pevonedistat to azacitidine and venetoclax in patients with RR-AML. Methods: This is a phase I multicenter study (NCT04172844) with 3 + 3 design to determine the safety and recommended phase 2 dose (RP2D) of pevonedistat, venetoclax and azacitidine in RR-AML. Patients aged 18 years or above with morphologically documented RR-AML, ECOG performance status 0-2 and adequate organ function were eligible. Exclusion criteria were isolated extramedullary relapse, hematopoietic stem cell transplantation (HSCT) within 100 days of enrollment, and active acute graft versus host disease. Previous therapy with hypomethylating agent (HMA) or venetoclax was not an exclusion. Treatment included azacitidine (75 mg/m2 daily x 7 days), venetoclax (400 mg daily x 28 days), and pevonedistat in escalating doses (10-20 mg/m2 IV days 1,3,5 of each cycle) in 28-day cycles. Pevonedistat was given at 10 mg/m2 dose in cohort 1, 15 mg/m2 in cohort 2 and 20 mg/m2 in cohort 3. Results: Sixteen patients with RR-AML participated in the study (15 evaluable for response). Median age was 73 years (61-91), 37.6% had secondary/therapy related AML, 56.3% received prior venetoclax/HMA and 18.1% had relapse after prior allogeneic HSCT. Most common grade 3 or higher adverse events included neutropenia (44%), thrombocytopenia (38%), febrile neutropenia (25%), anemia (25%), and sepsis (19%). There was 1 dose limiting toxicity (DLT) in cohort 1 (atrial fibrillation), but no subsequent DLT despite planned dose escalation. Pevonedistat 20 mg/m2 was established as the RP2D. The rate of CR/CRi/morphological leukemia free state (MLFS) was 40% (CR/CRi 33%) for the overall cohort and 85.7% in venetoclax/HMA naïve RR-AML with a median time to response of 1 cycle. Among patients achieving CR/CRi, 60% attained minimal residual disease negativity by flow cytometry. Correlative studies with BH3 mimetic profiling showed variable baseline sensitivity to BH3 mimetics and sequential western blot assays showed upregulation of PUMA (for two patients in CR) and NOXA (for one patient with MLFS). Higher levels of DNMT1 were seen in patients with CR or MLFS. One patient with CR also had evidence of leukemic stem cell/progenitor cell sensitivity to pevonedistat at 50-100 nM. Summary/Conclusion: Combining pevonedistat with venetoclax and azacitidine is safe and tolerable in patients with RR-AML. Dose escalation yielded encouraging efficacy with pevonedistat 20 mg/m2 as the RP2D.